The orthopoxviruses, smallpox (variola), ectromelia and to a lesser extent monkeypox virus have narrow host ranges but for others (vaccinia and cowpox viruses) the host range is much more extensive. In light of bioterrorism concerns and the question of how viruses "jump" into new host species (both major concerns of SERCEB), it is imperative to study and identify host gene networks that determine and regulate host range. However, little is known about host genes that determine permissiveness, restriction or clinical course of disease. To elucidate such host genes, we will screen a panel of genetically diverse, C57BL/6J and DBA/2J advanced recombinant inbred (BXD ARI) mice for susceptibility to infection beginning with cowpox and ectromelia virus to establish the system and thereafter monkeypox virus. These mice and relevant services are provided by the SAID Core E. The relative permissiveness of a given virus, coupled with the genetic profiling of the infected versus the uninfected animals and an advanced bioinformatic analysis (genenetwork.org) will identify specific host genes/pathways which are critical for resistance/susceptibility of the infections and provide us a better understanding of the relationship between host and pathogen. These results will provide insight into the design of new intervention strategies, new targets for antiviral therapies and provide clues as to how "species jumping" might occur and identify combinations of biomarkers of host susceptibility/resistance genes that can be used for prognostic purposes and a platform for the screening of other pathogens. We propose the following specific aims: Specific Aim 1: We will determine the extent by which variation in host genotype modulates the infection phenotype of Ectromelia, Cowpox and Monkeypox viruses. Infection conditions will be standardized and disease evaluated in parental and BXD mice;Specific Aim 2: We will map quantitative trait loci (QTL), define relevant known and novel networks of candidate genes and pathways that are likely to contribute to disease severity and. Specific Aim 3: We propose strategies to confirm and exploit the implicated genes/pathways to develop antivirals and intervention strategies